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Discovery of dual-acting HDAC inhibitors for the treatment of pancreatic cancer by combining drug synergy and molecular modeling
Get PDFPancreatic ductal adenocarcinoma (PDAC) is one of the most threatening and deadly cancers. The occurrence of
chemoresistance in PDAC plays an important role in the unfavorable survival rates, so there is an urgent need to
rapidly develop new pharmaceutical strategies to address this problem and improve treatment outcomes for
PDAC (1). Considering the numerous epigenetic alterations observed in PDAC, the use of epigenetic drugs, such
as histone deacetylase (HDAC) inhibitors, is a promising approach, especially when used in combination
therapies (2).
In this study, we investigated the potential of using drug sensitivity and basal gene expression data from
pancreatic cancer cell lines to develop a bioinformatic screening protocol to predict the available combinatorial
options for HDAC inhibitors, including sirtuin (SIRT) inhibitors. Experimental validation of the protocol in two
pancreatic cancer cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified synergies between HDAC
inhibitors and the sphingosine-1-phosphate (S1P) receptor agonist – fingolimod or HDAC inhibitors and the
Rho-associated protein kinase (ROCK) inhibitor – RKI-1447 (3).
The bioinformatic screening protocol developed to predict synergistic drug combinations in PDAC identified
several previously unknown interaction partners of HDAC inhibitors. The predicted interaction partners of
HDAC inhibitors, including ROCK, aurora kinase A inhibitor (AURKA), glutaminase inhibitor (GLS) and
WEE1 kinase inhibitor, were selected using structure-based molecular modeling for the development of novel
classes of dual-acting HDAC inhibitors. The novel dual inhibitors (HDAC/ROCK, SIRT/AURKA, HDAC/GLS
and HDAC/WEE1) were designed based on the known pharmacophore properties and molecular docking models
developed for the respective targets. The molecular docking study was performed using GOLD software. The
enzymes were prepared for the docking study using the online software Play Molecule-ProteinPrepare. The
docking results of the developed inhibitors showed a remarkable affinity to the specific targets. The critical parts
of the structures that produce the interactions crucial for the inhibition of HDAC1, HDAC6, ROCK1, ROCK2,
AURKA, GLS and WEE1 were identified. In conjunction with the drug synergy predictions, these designed
molecules also show great potential as promising structures for subsequent experimental evaluation. Taking all
these findings into account, the most aactive compounds were selected to be further synthesized and evaluated
using in vitro enzyme and cell assays.
References
1) A. McGuigan et al., World J Gastroenterol. 24, 4846–4861 (2018).
2) X.-S. Xiang, P.-C. Li, W.-Q. Wang, L. Liu, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1877, 188676
(2022).
3) N. Djokovic, A. Djuric, D. Ruzic, T. Srdic-Rajic, K. Nikolic, Pharmaceuticals. 16, 294 (2023)
Response to the Letter to the Editor concerning ‘Cost-effectiveness of velmanase alfa vs. bone marrow transplantation or no causal therapy in patients with mild to moderate alpha-mannosidosis’
Get PDFExploring fullerene derivatives for optoelectronic applications: synthesis and characterization study
No full textIn this study, we conducted a comprehensive investigation of newly synthesized fullerene derivatives developed for potential application in perovskite solar cells (PSCs). We explored three novel dihydrofuran-fused C60 fullerene derivatives (13, 14, and 15) that were specifically designed to enhance solubility and interaction with the substrate, fluorine-doped tin oxide (FTO). A comparative analysis was performed, with reference to the widely used phenyl-C61-butyric acid methyl ester (PCBM) and compound 12, from which 13, 14, and 15 are derived, to assess the impact of sugar units on materials properties. The synthesized compounds demonstrated significant solubility in common organic solvents, a critical factor in their potential application in wet-processed PSCs. Our investigation included electrochemical property analysis, thin film deposition, surface characterization, and electrochemical impedance spectroscopy (EIS). EIS measurements unveiled key insights into charge transfer properties at the electrode/electrolyte interface, making the compounds attractive candidates for electron transport layers (ETLs) in PSCs
Chemical Analysis and Investigation of Antimicrobial and Antibiofilm Activities of Prangos trifida (Apiaceae)
Get PDFPlants of the genus Prangos are intensively investigated as potential new sources of bioactive isolated products. In this work, the chemical composition of volatile constituents (essential oils and headspace volatiles) and dichloromethane extracts, as well as antimicrobial and antibiofilm activities of essential oils and MFDEs (methanol fractions of dichloromethane extracts) of Prangos trifida from Serbia, were investigated. Volatiles of roots, leaves, stems and fruits, and fatty acids and phytosterols in dichloromethane extracts of roots and fruits were analyzed by GC-FID-MS, whereas coumarins in MFDEs by LC–MS and some isolated coumarins by 1H-NMR. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations/minimum fungicidal concentrations (MBCs/MFCs) of essential oils and MFDEs were determined against 13 microorganisms. Antibiofilm activity was assessed against four microorganisms. Additionally, congo red and ergosterol binding assays were conducted to elucidate selected mechanisms of antibiofilm action in the case of Candida albicans. Total of 52 volatile constituents, 16 fatty acids, eight phytosterols and 10 coumarins were identified. Essential oils demonstrated significant activity, surpassing that of commercial food preservatives, against six tested molds from the Aspergillus, Penicillium and Trichoderma genera, as well as against bacteria Staphylococcus aureus and Bacillus cereus. Most of the oils strongly inhibited the formation of biofilms by S. aureus, Listeria monocytogenes and Escherichia coli. MFDEs exhibited noteworthy effects against B. cereus and the tested Aspergillus species, particularly A. niger, and significantly inhibited C. albicans biofilm formation. This inhibition was linked to a marked reduction in exopolysaccharide production, while antifungal mechanisms associated with ergosterol remained unaffected
Synthesis, Characterization, and Investigation of Anti-Inflammatory and Cytotoxic Activities of Novel Thiourea Derivatives of Naproxen
Get PDFThe objective of this study was to synthesize seven novel thiourea derivatives of naproxen (8–14), examine the anti-inflammatory activity of the newly synthesized compounds, investigate the cytotoxic potential of both sets of synthesized compounds (1–7 and 8–14), and select the most promising anti-inflammatory and antitumor drug candidates. The results of the in vivo anti-inflammatory study clearly showed that compounds 8 and 9 were capable of decreasing paw edema, as evident from a high percentage of inhibition (44.83% and 49.29%, respectively). In addition, the results of in vitro enzyme inhibition assays demonstrated that neither of the newly synthesized compounds reached 50% inhibition of 5-LOX at concentrations lower than 100 μM. In terms of antitumor potential, derivatives 3 and 8 exhibited strong cytotoxic effects on the HeLa cell line, suggesting the involvement of the extrinsic pathway of apoptosis. According to the overall results obtained for both sets of synthesized molecules, derivatives 4 and 8 can be underlined as molecules with the strongest anti-inflammatory activity, while derivatives 3 and 8 are the most promising cytotoxic agents
Complex global dynamics of conditionally stable slopes: effect of initial conditions
Get PDFIn the present paper, we investigate the effect of the initial conditions on the dynamics of the spring-block landslide model. The time evolution of the studied model, which is governed by a system of stochastic delay differential equations, is analyzed in the mean-field approximation, which qualitatively exhibits the same dynamics as the initial model. The results of the numerical analysis show that changing the initial conditions has different effects in different parts of the parameter space of the model. Namely, moving away from the fixed-point initial conditions has a stabilizing effect on the dynamics when the noise, the friction parameters a (higher values) and c as well as the spring stiffness k are taken into account. The stabilization manifests itself in a complete suppression of the unstable dynamics or a partial limitation of the effect of some friction parameters. On the other hand, the destabilizing effect of changing the initial conditions occurs for the lower values of the friction parameters a and for b. The main feature of destabilization is the complete suppression of the sliding regime or a larger parameter range with a transient oscillatory regime. Our approach underlines the importance of analyzing the influence of initial conditions on landslide dynamics.Supplementary material: [https://farfar.pharmacy.bg.ac.rs/handle/123456789/5562
Electrochemical Sensing of Cadmium and Lead Ions in Water by MOF-5/PANI Composites
Get PDFFor the first time, composites of metal-organic framework MOF-5 and conjugated polymer polyaniline (PANI), (MOF-5/PANI), prepared using PANI in its conducting (emeraldine salt, ES) or nonconducting form (emeraldine base, EB) at various MOF-5 and PANI mass ratios, were evaluated as electrode materials for the electrochemical detection of cadmium (Cd2+) and lead (Pb2+) ions in aqueous solutions. Testing of individual components of composites, PANI-ES, PANI-EB, and MOF-5, was also performed for comparison. Materials are characterized by Raman spectroscopy, scanning electron microscopy (SEM) and dynamic light scattering (DLS), and their electrochemical behavior was discussed in terms of their zeta potential, structural, morphology, and textural properties. All examined composites showed high electrocatalytic activity for the oxidation of Cd and Pb to Cd2+ and Pb2+, respectively. The MOF/EB-1 composite (71.0 wt.% MOF-5) gave the highest oxidation currents during both individual and simultaneous detection of two heavy metal ions. Current densities recorded with MOF/EB-1 were also higher than those of its individual components, reflecting the synergistic effect where MOF-5 offers high surface area for two heavy metals adsorption and PANI offers a network for electron transfer during metals’ subsequent oxidation. Limits of detection using MOF/EB-1 electrode for Cd2+ and Pb2+ sensing were found to be as low as 0.077 ppm and 0.033 ppm, respectively. Moreover, the well-defined and intense peaks of Cd oxidation to Cd2+ and somewhat lower peaks of Pb oxidation to Pb2+ were observed at voltammograms obtained for the Danube River as a real sample with no pretreatment, which implies that herein tested MOF-5/PANI electrodes could be used as electrochemical sensors for the detection of heavy metal ions in the real water samples
The impact of the aqueous phase on the physicochemical characteristics of nanoemulsions loaded with patent protected compound GL-II-73
No full textINTRODUCTION Temporal lobe epilepsy is characterized by seizures, but can also be associated with mental health problems for which there are no clear treatment regimens. A proprietary compound, GL-II-73 - (4R)-8-ethynyl-6-(2-fluorophenyl)-N,N,4-trimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide, a positive allosteric modulator of α5-containing γ-aminobutyric acid (GABA) receptors, has been shown to be effective in the treatment of these comorbidities [1]. ..
Udruženost polimorfizama gena za katehol-O- metiltransferazu sa terapijskim odgovorom i komplikacijama izazvanim levodopom kod Parkinsonove bolesti: Rezime sadašnjih saznanja
Get PDFCatechol-O-methyltransferase (COMT) is one of the cardinal enzymes in the degradation
of catecholamines and levodopa. Genetic variants of the COMT gene may affect COMT enzyme
activity. The most examined COMT gene polymorphism is the nonsynonymous single nucleotide
polymorphism (SNP) in exon 4 (Val108/158Met; rs4680). This highly functional polymorphism
is responsible for fourfold variations in enzyme activity and dopamine catabolism. Recent data
suggested that even synonymous SNPs of the COMT gene can lead to changes in enzyme activity.
Genetically determined COMT activity can affect an individual's response to levodopa therapy
and carries the risk of complications from prolonged levodopa use in Parkinson's disease (PD)
patients. Identifying at-risk individuals through genetic susceptibility markers could help to
prevent the development of levodopa-induced complications in PD.Katehol-O-metiltransferaza (engl. catechol-O-methyltransferase, COMT) je jedan od
glavnih enzima u razgradnji kateholamina i levodope. Genetske varijante COMT gena mogu
uticati na aktivnost COMT enzima. Polimorfizam COMT gena koji je najviše proučavan je
nesinonimni jednonukleotidni polimorfizam (engl. single nucleotide polymorphism, SNP) u
egzonu 4 (Val108/158Met; rs4680). Ovaj visoko funkcionalni polimorfizam odgovoran je za
četvorostruke varijacije u aktivnosti enzima i katabolizmu dopamina. Nedavni podaci sugerišu da
čak i sinonimni SNP COMT gena mogu da dovedu do promena u aktivnosti enzima. Genetski
određene razlike u COMT aktivnosti mogu uticati na odgovor pojedinca na terapiju levodopom i
nose rizik od komplikacija dugotrajne primene levodope kod pacijenata sa Parkinsonovom
bolešću (PB). Identifikacija osoba u riziku putem markera genetske osetljivosti može pomoći u
prevenciji komplikacija izazvanih levodopom kod PB
Current level of evidence for improvement of antidepressant efficacy and tolerability by pharmacogenomic-guided treatment: A Systematic review and meta-analysis of randomized controlled clinical trials
Get PDFThe aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression